To fulfill the roles the lymphatic system plays in body fluid regulation, macromolecular homeostasis, lipid absorption, immune function, it must transport lymph from the interstitium, along the lymphatic network, through the nodes, into the great veins of the neck. Lymphatic muscle utilizes a unique combination of tonic and phasic contractions and muscle contractile proteins to generate and control lymph flow/transport. Contraction of lymphatic muscle is driven and regulated by both physical and ionic events. Stretch of the lymphatic wall is the most well documented physical stimulator of lymphatic function. Lymphatic muscle ionic events drive the electrical activity and intracellular calcium to modulate contraction. However, the ionic mechanisms regulating lymphatic muscle contraction and how stretch activates them are relatively unknown. To gain a better understanding of the regulation of lymphatic function, we propose to investigate the ionic mechanisms of lymphatic muscle contraction and how they are affected by stretch in isolated rat mesenteric lymphatics. Dysfunctional lymphatics result in a wide range of clinical problems. This project will substantially advance our understanding of lymphatic biology and provide the basis for the eventual development of therapeutic strategies to diagnose and treat lymphatic contractile dysfunction. PUBLIC HEALTH RELEVANCE: To fulfill the roles the lymphatic system plays in body fluid and macromolecular regulation, lipid absorption and immune function, it transports lymph from the interstitium, along the lymphatic network, through the nodes, into the great veins of the neck using contractions of the lymphatic muscle to generate and control lymph flow. However, the ionic mechanisms regulating lymphatic muscle contraction and how stretch (the predominant physical factor that regulate lymph pumping) activates them are unknown. This project will substantially advance our understanding of lymphatic biology and provide the basis for the development of therapeutic strategies to treat lymphatic contractile dysfunction, which can result in a wide range of clinical problems.